Rotator cuff damage due to degeneration and/or injury is a common cause of significant pain and disability affecting the young and old alike in workplace, recreational, athletic, and aging environments. Different from most tendons, the supraspinatus tendon must regularly withstand a complex loading environment including multi-axial tension, compression, and shear, which makes study of this problem difficult. The complex loading is due to its anatomical structure, with non-uniaxial forces generated by the surrounding soft tissues, the coracoacromial arch, oblique insertion angles, and non-uniform fiber orientations. In order to understand, predict, prevent, and treat supraspinatus degeneration and injury, as well as to design tissue engineered replacement structures, it is critical to develop a complete understanding of the mechanical capability of this tissue in normal and altered conditions. Therefore, the objective of this research program is to rigorously evaluate anisotropic and nonlinear structure-function relationships in normal and degenerate supraspinatus tendons. Specifically, we propose the following 2 aims: Aim 1: Quantify nonlinear and anisotropic mechanical behavior and collagen fiber re-orientation of normal and degenerated human supraspinatus tendon under multiple loading modalities including: uniaxial tension in the fiber-aligned and transverse directions, biaxial tension, and planar shear. Quantify biochemical composition and histological grade at adjacent locations to the mechanical test samples. Aim 2: Develop and apply a nonlinear anisotropic constitutive model to predict tendon structure-function relationships. Explicitly incorporate fiber distribution and fiber re-orientation under load and the contribution of fiber stretch, extrafibrillar matrix, and fiber-matrix interactions to tendon function. Determine the model parameters using the biaxial and shear experimental data from Aim 1 and validate the model by predicting the uniaxial tension data. Correlate model parameters with composition measurements to complete the structure-composition-function quantification and test hypotheses for these relationships with region and degeneration. Knowledge of these relationships will provide important information towards understanding the fundamental mechanisms driving normal tissue adaptation and aging, disease processes and potential treatments, and the design of tissue engineered replacement structures. PUBLIC HEALTH RELEVANCE: Rotator cuff damage due to degeneration and/or injury is a common cause of significant pain and disability affecting the young and old alike in workplace, recreational, athletic, and aging environments. Treatment strategies aim to restore mechanical function;however, tendon anisotropic and nonlinear mechanical behaviors are not well established. Therefore, the objective of this research program is to determine quantitative anisotropic and nonlinear structure-function relationships in normal and degenerate supraspinatus tendons.